Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

• This invention concerns novel cyclic ether derivatives and more particularly novel cyclic ether derivatives which are inhibitors of the enzyme 5-lipoxygenase (hereinafter referred to as 5-LO).
• the invention also concerns processes for the manufacture of said cyclic ether derivatives and novel pharmaceutical compositions containing them. Also included in the invention is the use of said cyclic ether derivatives in the treatment of various inflammatory and/or allergic diseases in which the direct or indirect products of 5-LO catalysed oxidation of arachidonic acid are involved, and the production of new medicaments for such use.
• the cyclic ether derivatives described hereinafter are inhibitors of 5-LO, which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B 4 (LTB 4 ) and the peptido-lipid leukotrienes such as leukotriene C 4 (LTC 4 ) and leukotriene D 4 (LTD 4 ) and various metabolites.
• 5-LO physiologically active leukotrienes
• LTC 4 leukotriene C 4
• LTD 4 leukotriene D 4
• the biosynthetic relationship and physiological properties of the leukotrienes are summarised by G.W. Taylor and S.R. Clarke in Trends in Pharmacological Sciences, 1986, Z, 100-103.
• the leukotrienes and their metabolites have been implicated in the production and development of various inflammatory and allergic diseases such as arthritic diseases, asthma, allergic rhinitis, atopic dermatitis, psoriasis, cardiovascular and cerebrovascular disorders and inflammatory bowel disease.
• the leukotrienes are mediators of inflammatory diseases by virtue of their ability to modulate lymphocyte and leukocyte function.
• Other physiologically active metabolites of arachidonic acid, such as the prostaglandins and thromboxanes arise via the action of the enzyme cyclooxygenase on arachidonic acid.
• a cyclic ether derivative of the formula I (set out hereinafter) wherein Ar 1 is phenyl or naphthyl, or a 9- or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, and Ar 1 may optionally bear up to five substituents selected from amino, halogeno, hydroxy, cyano, oxo, thioxo, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoyl, fluoro-(1-4C)alkyl, cyano-(1-4C)alkyl, phenyl, benzoyl and phenyl
• alkyl includes both straight-chain and branched-chain alkyl groups.
• references to individual alkyl groups such as “propyl” are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as “isopropyl” are specificforthe branched-chain version only.
• An analogous convention applies to other generic terms.
• optically active or racemic forms by virtue of one or more substituents containing an asymmetric carbon atom
• the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting 5-LO.
• the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
• inhibitory properties against 5-LO may be evaluated using the standard laboratory techniques referred to hereinafter.
• a suitable value for Ar 1 when it is a 9- or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur is, for example, a 9- or 10-membered benzo-fused heterocyclic moiety such as indolyl, isoindolyl, benzimidazolyl, 1H-indazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 4H-1,4-benzoxazinyl or 4H-1,4-benzothiazinyl, or a hydrogenated derivative thereof such as indolinyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzothiazolyl, 1,2-dihydroquinolyl
• the heterocyclic moiety may be attached through any available position including from either of the two rings of the bicyclic heterocyclic moiety and including through an available nitrogen atom.
• the heterocyclic moiety may bear a suitable substituent such as, for example, a (1-4C)alkyl, phenyl, benzoyl or phenyl-(1-4C)alkyl substituent on an available nitrogen atom.
• Suitable values for substituents which may be present on Ar 1 or Ar 2 , or on a phenyl, benzoyl or phenyl-(1-4C)alkyl substituent on Ar 1 include, for example:
• Suitable values for substituents which may be present on Ar 1 include, for example:
• a suitable value for A 1 when it is (1-3C)alkylene is, for example, methylene, ethylene or trimethylene.
• a suitable value for Ar 2 when it is phenylene is, for example 1,3-phenylene or 1,4-phenylene.
• a suitable value for Ar 2 when it is pyridylene is, for example 3,5- or 2,6-pyridylene.
• a suitable value for a (2-4C)alkanoylamino substituent which may be present on Ar 2 is, for example, acetamido, propionamido or butyramido.
• a suitable value for R 1 when it is (1-4C)alkylthio is, for example, methylthio, ethylthio, propylthio, isopropylthio or butylthio; when it is (1-4C)alkylsulphinyl is, for example, methylsulphinyl, ethylsulphinyl, propylsulphinyl, isopropylsulphinyl or butylsulphinyl; when it is (1-4C)alkylsulphonyl is, for example, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl and butylsulphonyl; when it is (1-4C)alkylamino is, for example, methylamino, ethylamino, propylamino, isopropylamino or butylamino; and when it is di-[(1-4C)
• a suitable value for R 1 when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl or isobutyl; when it is (1-4C)alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or butoxycarbonyl; when it is N-(1-4C)alkylcarbamoyl is, for example, N-methylcarbamoyl, N-ethylcarbamoyl or N-propylcarbamoyl; when it is N,N-di -[ (1-4C)alkyl]carbamoyl is, for example, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or N,N-dipropylcarbamoyl; when it is hydroxy-(1-4C)alkyl is, for example
• R 2 and R 3 together form a group of the formula -A 2 -X 2 -A 3 - which, together with the carbon atom to which A 2 and A3 are attached, defines a ring having 5 to 7 ring atoms then a suitable value for A 2 or A3, which may be the same or different, when each is (1-3C)alkylene is, for example, methylene, ethylene ortrimethylene.
• Suitable values for the substituents which may be present on said 5- to 7-membered ring include for example:- for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl and isobutyl; for (1-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy.
• a suitable pharmaceutically-acceptable salt of a novel compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
• a suitable pharmaceutically-acceptable salt of a novel compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
• an alkali metal salt for example a sodium or potassium salt
• an alkaline earth metal salt for example a calcium or magnesium salt
• an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation
• a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(
• novel compounds of the invention are, for example, cyclic ether derivatives of the formula I wherein:-
• a preferred compound of the invention comprises a cyclic ether derivative of the formula I wherein Ar 1 is phenyl or naphth-2-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, 2-cyanoprop-2-yl, phenyl and benzoyl and wherein said phenyl or benzoyl substituents may optionally bear a substituent selected from chloro, methyl and methoxy;
• a 1 is a direct link to X 1 , or is methylene;
• X 1 is oxy, thio, sulphinyl or sulphonyl;
• Ar 2 is 1,3-phenylene or 1,4-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, hydroxy, amino, nitro, ureido, methoxy, dimethylamino, tri
• a further preferred compound of the invention comprises a cyclic ether derivative of the formula I wherein Ar 1 is 2-oxoindolin-5-yl, 2,3-dioxoindolin-5-yl, 2-oxo-2,3-dihydrobenzimidazol-5-yl, 2-oxo-2,3-dihyd- robenoxazol-5-yl, 2-oxo-2,3-dihydrobenzothiazol-5-yl, 2-oxo-1,2-dihydroquinolin-3-yl, 2-oxo-1,2-dihydro- quinolin-6-yl, 2-oxo-1,2-dihydroquinolin-7-yl, 3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl or 3-oxo-2,3-dihydro-4H-1,4-benzothiazol-7-yl, which may optionally bear one, two or three substituents selected from fluoro,
• a further preferred compound of the invention comprises a cyclic ether derivative of the formula I wherein Ar 1 is naphth-2-yi which may optionally bear one or two substituents selected from fluoro, chloro, methyl, methoxy and trifluoromethyl, or Ar 1 is 2-oxo-1,2-dihydroquinolin-6-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl; A 1 is a direct link to X 1 , or is methylene; X 1 is oxy, thio, sulphinyl or sulphonyl; Ar 2 is 1,3-phenylene which may optionally bear a substituent selected from fluoro, chloro and trifluoromethyl; R 1 is methylthio, ethylthio, propylthio, isopropylthio, tert-butylthio, methylsulphinyl, ethylsulphinyl, propy
• a further preferred compound of the invention comprises a cyclic ether derivative of the formula I wherein Ar 1 is phenyl which may optionally bear a substituent selected from fluoro, chloro, methyl, tert-butyl, phenyl and benzoyl, and wherein said phenyl or benzoyl substituent may optionally bear a chloro substituent, or Ar 1 is naphth-2-yl which may optionally bear a substituent selected from fluoro, chloro and methyl;
• a 1 is a direct link to X 1 , or is methylene;
• X 1 is oxy, thio, sulphinyl or sulphonyl;
• Ar 2 is 1,3-phenylene which may optionally bear one or two substituents selected from fluoro and trifluoromethyl;
• R 1 is methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl or
• a further preferred compound of the invention comprises a cyclic ether derivative of the formula I wherein Ar 1 is phenyl which may optionally bear a substituent selected from fluoro, chloro, methyl, tert-butyl, phenyl and benzoyl, and wherein said phenyl or benzoyl substituent may optionally bear a chloro substituent, or Ar 1 is naphth-2-yl which may optionally bear a substituent selected from fluoro, chloro and methyl; A 1 is a direct link to X 1 , or is methylene; X 1 is oxy, thio, sulphinyl or sulphonyl; Ar 2 is 1,3-phenylene which may optionally bearone or two substituents selected from fluoro and trifluoromethyl; R 1 is cyano, methoxycarbonyl, ethoxycarbonyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl
• a further preferred compound of the invention comprises a cyclic ether derivative of the formula I wherein Ar 1 is 1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-yi, 3-methyl-2-oxo-2,3-dihydrobenzothiazol-6-yl, 1-methyl-2-oxo-1,2-dihydroquinolin-6-yl, 1-ethyl-2-oxo-1,2-dihydroquinolin-6-yl, 4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl or 2,2,4-trimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl;
• a 1 is a direct link to X l , or is methylene;
• X 1 is oxy, thio, sulphinyl or sulphonyl;
• Ar 2 is 1,3-phenylene which may
• a further preferred compound of the invention comprises a cyclic ether derivative of the formula I wherein Ar 1 is 1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-yl, 3-methyl-2-oxo-2,3-dihydrobenzothiazol-6-yl, 1-methyl-2-oxo-1,2-dihydroquinolin-6-yl, 1-ethyl-2-oxo-1,2-dihydroquinolin-6-yl, 4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl or 2,2,4-trimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl;
• a 1 is a direct link to X 1 , or is methylene;
• X 1 is oxy, thio, sulphinyl or sulphonyl;
• Ar 2 is 1,3-phenylene which may optional
• a further preferred compound of the invention comprises a cyclic ether derivative of the formula I wherein Ar 1 is naphth-2-yl which may optionally bear a fluoro substituent, orAr 1 is 1-methyl-2-oxo-1,2-dihydro- quinolin-6-yl; A 1 is methylene and X 1 is oxy; Ar 2 is 1,3-phenylene or 5-fluoro-1,3-phenylene; R 1 is methylthio, ethylthio, isopropylthio, tert-butylthio, methylsulphinyl, hydrogen, formyl, cyano, methyl, ethyl, ethoxycarbonyl, hydroxymethyl, 1-hydroxyethyl, 2,2,2-trifluoroethylthio, acetyl or methoxymethyl; and R 2 and R 3 together form a group of the formula -A 2 -X 2 -A 3 - which, together with the carbon atom to which each of
• Specific especially preferred compounds of the invention include the following cyclic ether derivatives of the formula I, or pharmaceutically-acceptable salts thereof:-4-methylthio-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran and 4-ethoxycarbonyl-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran.
• cyclic ether deriva- fives of the formula 1, or pharmaceutically-acceptable salts thereof -4-acetyl-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran, 4-[5-fluoro-3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-3,4,5,6-tetrahydro-2H-pyran, 4-ethyl-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran, (2RS,4RS)-4-ethyl-4-[5-fluoro-3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-2-methyltetrahydropyran and
• a compound of the invention comprising a cyclic ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of structurally-related compounds. Such procedures are provided as a further feature of the invention and are illustrated by the following representative examples in which, unless otherwise stated, Ar 1 , A 1 , X 1 , Ar 2 , R 1 , R 2 and R 3 have any of the meanings defined hereinbefore.
• a suitable displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, iodo, methane-sulphonyloxy or toluene-p-sulphonyloxy group.
• a suitable base for the coupling reaction is, for example, an alkali or alkaline earth metal carbonate, (1-4C)alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, sodium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride.
• the coupling reaction is conveniently performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 100°C.
• a suitable inert solvent or diluent for example N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 100°C.
• reaction may be performed in the presence of a suitable catalyst, for example a metallic catalyst, for example palladium(O) or copper(I) such as tetrakis(triphenylphosphine)palladium; cuprous chloride or cuprous bromide.
• a suitable catalyst for example a metallic catalyst, for example palladium(O) or copper(I) such as tetrakis(triphenylphosphine)palladium; cuprous chloride or cuprous bromide.
• a suitable protecting group for an amino or alkylamino group is, for example, an acyl group for example a (2-4C)alkanoyl group (especially acetyl), a (1-4C)alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), an arylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroyl group (especially benzoyl).
• the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or alkoxycarbonyl or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal.
• a suitable protecting group for a hydroxy group is, for example, an acyl group, for example a (2-4C)alkanoyl group (especially acetyl), an aroyl group (especially benzoyl) or an arylmethyl group (especially benzyl).
• the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal.
• the starting materials of the formula Ar 1 -A 1 -X 1 -H and of the formula II may be obtained by standard procedures of organic chemistry.
• the coupling reaction is conveniently performed in a suitable inert solvent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 100°C.
• the reaction may conveniently be performed in the presence of a suitable catalyst as defined hereinbefore.
• the starting materials of the formula Ar 1 -A 1 -Z and of the formula III may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples which are provided for the purpose of illustration only. Other necessary starting materials are obtainable by analogous procedures to those described or by modifications thereto which are within the ordinary skill of an organic chemist.
• a suitable protecting group for an imino group is, for example, any of the protecting groups defined hereinbefore for an amino or alkylamino group.
• the starting material of the formula IV may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples which are provided for the purpose of illustration only.
• a suitable oxidising agent is, for example, any agent known in the art for the oxidation of thio to sulphinyl and/or sulphonyl, for example, hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic or peroxyacetic acid), an alkali metal peroxysulphate (such as potassium peroxymonosulphate), chromium trioxide or gaseous oxygen in the presence of platinum.
• the oxidation is generally carried out under as mild conditions as possible and with the required stoichiometric amount of oxidising agent in order to reduce the risk of over oxidation and damage to other functional groups.
• the reaction is carried out in a suitable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature, for example, at or near ambient temperature, that is in the range 15 to 35°C.
• a milder oxidising agent may also be used, for example sodium or potassium metaperiodate, conveniently in a polar solvent such as acetic acid or ethanol.
• a compound of the formula I containing a sulphonyl group it may be obtained by oxidation of the corresponding sulphinyl compound as well as of the corresponding thio compound.
• a suitable acylating agent is, for example, any agent known in the artforthe acylation of amino to acylamino, for example an acyl halide, for example a (2-6C)alkanoyl chloride or bromide, in the presence of a suitable base, an alkanoic acid anhydride, for example a (2-6C)alkanoic acid anhydride, or an alkanoic acid mixed anhdride, for example the mixed anhydride formed by the reaction of an alkanoic acid and a (1-4C)alkoxycarbonyl halide, for example a (1-4C)a!koxycarbonyi chloride, in the presence of a suitable base.
• an acyl halide for example a (2-6C)alkanoyl chloride or bromide
• an alkanoic acid anhydride for example a (2-6C)alkanoic acid anhydride
• an alkanoic acid mixed anhdride for example the mixed anhydride formed by the reaction
• reaction is carried out in a suitable solvent or diluent such as methylene chloride, acetone, tetrahydrofuran ortert-butyl methyl ether and at a temperature, for example, at or near ambient temperature, that is in the range 15 to 35°C.
• a suitable base when it is required is, for example, pyridine, 4-dimethylaminopyridine, triethylamine, ethyidiisop- ropylamine, N-methylmorpholine, an alkali metal carbonate, for example potassium carbonate, or an alkali metal carboxylate, for example sodium acetate.
• a suitable alkylating agent is, for example, any agent known in the art for the alkylation of an available nitrogen atom, or of hydroxy to alkoxy, for example an alkyl or substituted alkyl halide, for example a (1-6C)alkyl chloride, bromide or iodide or a substituted (1-4C)alkyl chloride, bromide or iodide, in the presence of a suitable base.
• a suitable base for the alkylation reaction is, for example, an alkali or alkaline earth metal carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride.
• the alkylation reaction is preferably performed in a suitable inert solvent ordiluent, for example N,N-dimethylformamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150°C, conveniently at or near ambient temperature.
• a suitable inert solvent ordiluent for example N,N-dimethylformamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran
• a pharmaceutically-acceptable salt of a novel compound of the formula When a pharmaceutically-acceptable salt of a novel compound of the formula is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure.
• an optically active form of a compound of the formula I it may be obtained by carrying out one of the aforesaid procedures using an optically active starting material, or by resolution of a racemic form of said compound using a conventional procedure.
• novel compounds of the formula I are inhibitors of the enzyme 5-LO.
• the effects of this inhibition may be demonstrated using one or more of the standard procedures set out below:-
• the compound 4-methylthio-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran has an IC 50 of 0.05 ⁇ M against LTB 4 in test b), and an oral ED 50 of 8mg/kg versus LTB 4 in test g); and the compound 4-ethoxycarbonyl-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)tetrahydropyran has an IC 50 of 0.05 ⁇ M aganst LTB 4 in test b).
• those compounds of the formula I which are particularly preferred have an IC 50 of ⁇ 1 ⁇ M against LTB 4 in test b), and an oral ED so of ⁇ 100 mg/kg against LTB 4 in tests c) and/or g).
• These compounds are examples of compounds of the invention which show selective inhibitory properties for5-LO as opposed to cyclooxygenase, which selective properties are expected to impart improved therapeutic properties, for example, a reduction in or freedom from the gastrointestinal side-effects frequently associated with cyclooxygenase inhibitors such as indomethacin.
• a pharmaceutical composition which comprises a cyclic ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
• the composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension.
• the above compositions may be prepared in a conventional manner using conventional excipients.
• the amount of active ingredient (that is a cyclic ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
• a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
• Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
• a cyclic ether derivative of the formula 1, or a pharmaceutically-acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.
• the invention also includes a method of treating a disease or medical condition mediated alone or in part by one or more leukotrienes which comprises administering to a warm-blooded animal requiring such treatment an effective amount of an active ingredient as defined above.
• the invention also provides the use of such an active ingredient in the production of a new medicament for use in a leukotriene mediated disease or medical condition.
• the size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
• compounds of the formula I are useful in treating those allergic and inflammatory conditions which are due alone or in part to the effects of the metabolites of arachidonic acid arising by the linear (5-LO catalysed) pathway and in particular the leukotrienes, the production of which is mediated by 5-LO.
• such conditions include, for example, asthmatic conditions, allergic reactions, allergic rhinitis, allergic shock, psoriasis, atopic dermatitis, cardiovascular and cerebrovascular disorders of an inflammatory nature, arthritic and inflammatory joint disease, and inflammatory bowel diseases.
• a daily dose in the range for example, 0.5mg to 75mg per kg body weight is received, given if required in divided doses.
• a parenteral route is employed.
• a dose in the range for example, 0.5mg to 30 mg per kg body weight will generally be used.
• a dose in the range for example, 0.5 mg to 25 mg per kg body weight will be used.
• the compounds of the formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the enzyme 5-LO. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
• the compounds of the formula I have certain cytoprotective effects, for example they are useful in reducing or suppressing certain of the adverse gastrointestinal effects of the cyclooxygenase inhibitory non-steroidal anti-inflammatory agents (NSAIA), such as indomethacin, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam.
• NSAIA cyclooxygenase inhibitory non-steroidal anti-inflammatory agents
• co-administration of a 5-LO inhibitor of the formula I with a NSAIA can result in a reduction in the quantity of the latter agent needed to produce a therapeutic effect, thereby reducing the likelihood of adverse side-effects.
• a pharmaceutical composition which comprises a cyclic ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof as defined hereinbefore, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent (such as mentioned above), and a pharmaceutically-acceptable diluent or carrier.
• cytoprotective effects of the compounds of the formula I may be demonstrated, for example in a standard laboratory model which assesses protection against indomethacin-induced or ethanol-induced ulceration in the gastrointestinal tract of rats.
• compositions of the invention may in addition contain one or more therapeutic or prophylactic agents known to be of value for the disease under treatment
• a known platelet aggregation inhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergic blocker or a vasodilator may usefully also be present in a pharmaceutical composition of the invention for use in treating a heart or vascular disease or condition.
• an anti-histamine, steroid such as beclomethasone dipropionate
• sodium cromoglycate sodium cromoglycate
• phosphodiesterase inhibitor or a beta-adrenergic stimulant may usefully also be present in a pharmaceutical composition of the invention for use in treating a pulmonary disease or condition.
• the 4-mercapto-4-[3-(naphth-2-y)methoxy)pheny)]tetrahydropyran used as a starting material was obtained as follows:-A Grignard reagent was prepared by heating a mixture of 3-(naphth-2-yimethoxy)bromobenzene (3 g), magnesium powder (0.23 g) and THF (12 ml) to 30°C for 1.5 hours. The reagent was cooled to 20°C and a solution of tetrahydropyran-4-one (0.88 mi) in THF (5 mi) was added dropwise. The mixture was heated to 30°C for 15 hours, evaporated and the residue was partitioned between ethyl acetate and water.
• the 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one, used as a starting material was obtained as follows:-A mixture of 1,2-dihydro-1,6-dimethylquinolin-2-one (4.4 g; Helv. Chim. Acta., 1970, 53, 1903), N-bromosuccinimide (4.53 g), azobisisobutyronitrile (0.01 g) and carbon tetrachloride (75 ml) was heated to reflux for 3 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO 4 ) and evaporated.
• the 4-ethoxycarbonyl-4-(3-hydroxyphenyl)tetrahydropyran used as a starting material was obtained as follows:-A mixture of 3-hydroxyphenylacetic acid (10 g), ethanol (150 ml) and concentrated sulphuric acid (0.5 ml) was stirred .at ambient temperature for 16 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic phase was washed with water and brine, dried (MgSO 4 ) and evaporated. The residue was purified by column chromatography using initially methylene chloride and then increasingly polar mixtures of methylene chloride and acetone as eluent. There was thus obtained ethyl 3-hydroxyphenylacetate (11.4 g, 96%), IR Spectrum 1690-1740 cm- 1.
• Example 2 The procedure described in Example 2 was repeated except that 2-bromomethyl-7-fluoronaphthalene was used in place of 6-bromomethyl-1-methyl-1,2-dihydroquinotin-2-one. There was thus obtained 4-ethoxycarbonyl-4-[3-(7-fluoronaphth-2-ylmethoxy)phenyl]-tetrahydropyran in 76% yield, m.p. 91-92°C. Elemental Analysis: Found C, 73.0; H, 6.2; C 25 H 25 FO 4 requires C, 73.5; H, 6.1 %.
• the 2-bromomethyl-7-fluoronaphthalene used as a starting material was obtained as follows:-3-Fluorobenzyl chloride was reacted with acetylacetaldehyde dimethyl acetal using the procedure described for the corresponding reaction of 3-methylbenzyl chloride (Synthesis, 1974, 566). There was thus obtained 4-(3-fluorophenyl)-3-hydroxy-3-methylbutanai dimethyl acetal (b.p. 125-135°C at 0.25 mm Hg). A mixture of the material so obtained (15 g), glacial acetic acid (60 ml) and hydrobromic acid (48% w/v. 48 mi) was heated on a steam bath for 1 hour. The mixture was evaporated and the residue was purified by column chromatography using petroleum ether (b.p. 60-80°C) as eluent. There was thus obtained 7-fluoro-2-methylnaphthalene (4 g).
• the 3-hydroxyphenylacetonitrile used above was obtained as follows:-A mixture of m-cresol (10.8 g), tert-butyldimethylsilyl chloride (15 g), imidazole (6.8 g) and DMF (100 ml) was stirred at ambient temperature for 5 hours. The mixture was partitioned between diethyl ether and water. The organic phase was washed with 2N aqueous sodium hydroxide solution and brine, dried (MgSO 4 ) and evaporated. There was thus obtained 3-(tert-butyldimethylsilyloxy)toluene (18.2 g, 82%) as a liquid.
• Tetrabutylammonium cyanide (24.6 g) was added and the mixture was stirred at 0°C for 1.5 hours and at ambient temperature for 2.5 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and petroleum ether (b.p. 40-60°C) as eluent. There was thus obtained 3-(tert-butyl- dimethylsilyloxy)phenylacetonitrile (8 g, 42%) as an oil.
• Tetrabutylammonium fluoride (1.6M in THF, 15 ml) was added to a solution of the acetonitrile so obtained (4 g) in THF (15 ml) and the mixture was stirred at ambient temperature for 75 minutes. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried (MgS0 4 ) and evaporated. There was thus obtained 3-hydroxyphenylacetonitrile (1.85 g, 86%), IR Spectrum 2280 cm- 1 .
• Example 2 The procedure described in Example 2 was repeated except that 4-hydroxymethyl-4-(3-hydroxyphenyl)tetrahydropyran was used in place of 4-ethoxycarbonyl-4-(3-hydroxyphenyl)tetrahydropyran. There was thus obtained 4-hydroxymethyl-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 71% yield, m.p. 61°C.
• the 4-hydroxymethyl-4-(3-hydroxyphenyl)tetrahydropyran used as a starting material was obtained as follows:-A solution of ethyl 3-benzyloxyphenylacetate (0.45 g) in diethyl ether (2 ml) was added to a stirred suspension of lithium aluminium hydride (0.17 g) in diethyl ether (15 ml) and the mixture was stirred at ambient temperature for 10 minutes. Water (10 ml) was cautiously added dropwise to destroy the excess of reducing agent. The mixture was extracted with diethyl ether. The organic phase was dried (MgSO 4 ) and evaporated. There was thus obtained 4-(3-benzyloxyphenyl)-4-hydroxymethyltetrahydropyran (0.375 g) as an oil.
• Trifluoromethanesulphenic acid (0.2 ml) was added dropwise to a solution of 4-(3-benzyloxy-5-fluorophenyl)-4-hydroxytetrahydropyran (1.2 g) in methanethiol (10 ml) and the mixture was stirred at ambient temperature for 10 minutes.
• Boron trifluoride etherate (5.6 ml) was added and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between water and diethyl ether. The organic phase was washed with water and with a saturated aqueous sodium bicarbonate solution, dried (MgSO 4 ) and evaporated.
• the 4-(1-hydroxyethyl)-4-(3-hydroxyphenyl)tetrahydropyran used as a starting material, was obtained as follows:- A solution of oxalyl chloride (1.463 mi) in methylene chloride (5 ml) was added dropwise to a stirred mixture of DMSO (2.38 ml) and methylene chloride (5 ml) which had been cooled to -70°C. The mixture was stirred at -65°C for 15 minutes. A solution of 4-(3-benzyloxyphenyl)-4-hydroxymethyltetrahydropyran (5 g) in methylene chloride (5 ml) was added dropwise to the mixture which was maintained at a temperature of-60°C.
• Methylmagnesium bromide (3M in diethyl ether, 2 ml) was added dropwise to a solution of a portion (1.184 g) of the 4-formyltetrahydropyran so obtained in THF (20 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous ammonium chloride solution. The organic phase was washed with water and with brine, dried (MgSO 4 ) and evaporated. The residue was purified by column chromatography using initially methylene chloride and then a 5:1 v/v mixture of methylene chloride and diethyl ether as eluent. There was thus obtained 4-(3-benzyloxyphenyl)-4-(l-hydroxyethyl)tetrahydropyran (0.96 g, 77%), m.p. 119°C.
• the 4-formyl-4-(3-hydroxyphenyl)tetrahydropyran used as a starting material, was obtained as follows:-A mixture of 4-(3-benzyloxyphenyl)-4-formyltetrahydropyran (1 g), 10% palladium-on-charcoal catalyst (0.15 g), ethyl acetate (10 ml) and ethanol (20 ml) was stirred under 2.7 atmospheres pressure of hydrogen for 16 hours. The mixture was filtered and the filtrate was evaporated.
• the 4-acetyl-4-(3-hydroxyphenyl)tetrahydropyran used as a starting material, was obtained as follows:-The procedure described in the first paragraph of the portion of Example 14 which is concerned with the preparation of starting materials was repeated except that 4-(1-hydroxyethyl)-4-(3-hydroxyphenyl)tetrahydropyran was used in place of4-(3-benzyloxyphenyl)-4-hydroxymethyltetrahydropyran. There was thus obtained the required starting material in 77% yield, m.p. 120-121°C.
• the 4-(5-fluora-3-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran used as a starting material, was obtained as follows:-Sodium hydride (50% w/w dispersion in mineral oil, 2.11 g) was added portionwise to a stirred solution of 4-(3-benzyloxy-5-fluorophenyl ⁇ -4-hydroxytetrahydropyran (12.1 g) in THF (150 ml). The mixture was stirred at ambient temperature for 1 hour, cooled in an ice-bath and methyl iodide (3.75 ml) was added dropwise.
• the 4-(3-hydroxyphenyl)-4-methyltetrahydropyran used as a starting material, was obtained as follows:-A mixture of iodine (1.91 g), imidazole (0.68 g), triphenylphosphine (1.97 g), acetonitrile (5 ml) and bis(2-methoxyethyl ether (15 ml) was stirred at ambient temperature for 1 hour. A solution of 4-(3-benzyloxyphenyl)-4-hydroxymethyltetrahydropyran (1.5 g) in acetonitrile (2 ml) was added and the mixture was heated to 110°C for 6 hours.
• the 4-ethyl-4-(3-hydroxyphenyl)tetrahydropyran used a starting material, was obtained as follows:- n-Butyl-lithium (1.6M in hexane, 1.375 ml) was added dropwise to a solution of methyltriphenylphosphonium bromide (0.786 g) in a mixture of THF (15 ml) and diethyl ether (2 ml). The mixture was stirred at ambient temperature for 2 hours. The solution so obtained was added dropwise to a solution of 4-(3-benzyloxyphenyl ⁇ -4-formyltetrahydropyran (0.592 g) in diethyl ether (10 ml) and the mixture was stirred at ambient temperature for 4 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by
• the (2RS,4RS)-4-ethyl-4-(5-fluoro-3-hydroxyphenyl)-2-methyltetrahydropyran used as a starting material, was obtained as follows:-A mixture of iodine (115.5 g), imidazole (41.2 g), triphenylphosphine (159 g), acetonitrile (200 mi) and diethyl ether (500 ml) was stirred at ambient temperature for 30 minutes. A solution of 2-methyl-3-oxapentane-1,5-diol (J.C.S.
• n-Butyl-lithium (1.6 M in hexane, 1.16 mi) was added dropwise to a solution of methyltriphenylphosphonium bromide (0.664 g) in THF (10 ml) which had been cooled to -70°C. The mixture was stirred at -70°C for 1 hours. A solution of the 4-formyltetrahydropyran so obtained in THF (2 ml) was added dropwise and the mixture was stirred at -70°C for 30 minutes. The mixture was allowed to warm to ambient temperature. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using methylene chloride as eluent. There was thus obtained (2RS,4RS)-4-(3-benzyloxy-5-fluorophenyl)-2-methyl-4-vinyltetrahydropyran (0.4 g, 79%), as an oil.
• the above formulations may be obtained by conventional procedures well in the pharmaceutical art
• the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
• the aerosol formulations (h)-(k) may be used in conjunction with standard, metered dose aerosol dispensers, and the suspending agent sorbitan trileate and soya lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.

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